Process for the Preparation of Hexahydroisoquinolines from 1,2,3,4-Tetrahydroisoquinolines

ABSTRACT

The present invention is directed to processes for the synthesis of morphinans. In particular, a process for the asymmetric reduction of an imine moiety in a 3,4-dihydroisoquinoline to produce a tetrahydroisoquinoline, followed by a Birch reduction to produce a hexahydroisoquinoline. In various embodiments, the 3,4-dihydroisoquinoline contains a phenol moiety protected with a labile protecting group. In other embodiments, the imine reduction reaction mixture contains silver tetrafluoroborate.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 12/518,430 filed on Jun. 10, 2009 and entitled “PREPARATION OF TETRAHYDROISOQUINOLINES FROM DlHYDROISOQUINOLINES”, which claims priority to PCT application of PCT/US2007/025262, filed Dec. 10, 2007 and entitled “PREPARATION OF HEXAHYDROISOQUINOLINES FROM DIHYDROISOQUINOLINES”, which claims the benefit of U.S. Provisional Application No. 60/874,456 filed Dec. 12, 2006—

FIELD OF THE INVENTION

The present invention generally relates to processes for the synthesis of intermediates used to prepare morphinans. More specifically, the invention is directed to the synthesis of hexahydroisoquinolines and their analogs from dihydroisoquinolines.

BACKGROUND OF THE INVENTION

Hexahydroisoquinoline and its derivatives are important synthetic intermediates to many morphinan compounds including burprenorphine, codeine, etorphine, hydrocodone, hydromorphone, morphine, nalbuphine, nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. Generally, these compounds are analgesics, which are used extensively for pain relief in the field of medicine due to their action as opiate receptor agonists. However, nalmefene, naloxone and naltrexone are opiate receptor antagonists; they are used for reversal of narcotic/respiratory depression due to opiate receptor agonists.

Rice (U.S. Pat. No. 4,521,601) discloses the reduction of a dihydroisoquinoline to a tetrahydroisoquinoline by contacting the dihydroisoquinoline with sodium cyanoborohydride or sodium borohydride in refluxing 45% methanol for 1.5 hours. Rice further discloses Birch reduction of a tetrahydroisoquinoline to a hexahydroisoquinoline with lithium or sodium in liquid ammonia at −55° C. to −65° C. for 4 hours, then at −75° C. until none of the starting tetrahydroisoquinoline remains by thin layer chromatography. Because the borohydride reduction of a dihydroisoquinoline occurs in an achiral environment, the resulting tetrahydroisoquinoline must be resolved before further reaction. This resolution adds an extra step and reduces the yield of the desired enantiomer as half of the product has the undesired stereochemistry.

Uematsu et al. (J. Am. Chem. Soc. 1996, 113, 4916-4917) and Meuzelaar, et al. (Eur. J. Org. Chem. 1999, 2315-2321) disclose the asymmetric reduction of a dihydroisoquinoline with a chiral ruthenium catalyst in the presence of a 5:2 formic acid-triethylamine azeotropic mixture of salts in various aprotic solvents These transformations typically have a reaction time of about 3 hours. Thus, more efficient processes having higher yields and enantiomeric excesses are desirable.

SUMMARY OF THE INVENTION

Among the various aspects of the invention is a process for the preparation of a 1,2,3,4-tetrahydroisoquinoline corresponding to Formula 700 comprising treating a 3,4-dihydroisoquinoline corresponding to Formula 600 with an asymmetric catalyst in the presence of silver tetrafluoroborate, and a hydrogen source. The chemical structures corresponding to Formulae 600 and 700 are

wherein R₁, and R₇ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₁₁₁; R₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₁; R₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₁; R₄ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₁; R₅ and R₆ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₅₁₁; R₁₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₁₂₁; R₁₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₅₁₁; R₁₇ is hydrogen, or acyl; R₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; R₂₁₁ is hydrogen, hydrocarbyl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄; R₂₁₂, R₂₁₃, and R₂₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₃₁₁ is hydrogen, hydrocarbyl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄; R₃₁₂, R₃₁₃, and R₃₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₄₁₁ is hydrogen, hydrocarbyl, —C(O)R₄₁₂, —C(O)NHR₄₁₃, or —SO₂R₄₁₄; R₄₁₂, R₄₁₃, and R₄₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₅₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and R₁₂₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl.

Another aspect is a process for the preparation of a tetrahydroisoquinoline corresponding to Formula 701 comprising treating a 3,4-dihydroisoquinoline corresponding to Formula 601 with an asymmetric catalyst in the presence of a hydrogen source. The chemical structures corresponding to Formulae 601 and 701 are

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, R₁₃, R₁₇, R₁₁, R₂₁₁, R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₁, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₁, R₄₁₃, R₄₁₄, R₅₁₁, and R₁₂₁ are as defined above in connection with Formulae 600 and 700; R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than methyl; and wherein at least one of R₂, R₃, or R₄ is —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁₂, —OC(O)NHR₄₁₃, or —OSO₂R₄₁₄.

Yet another aspect is a process for the preparation of a hexahydroisoquinoline corresponding to Formula 800 comprising reducing a tetrahydroisoquinoline corresponding to Formula 704

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, R₁₃, R₁₇, R₁₁₁, R₂₁₁, R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₁, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₁, R₄₁₃, R₄₁₄, R₅₁₁, and R₁₂, are as defined above in connection with Formulae 600 and 700; R₂₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₅; R₃₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₆; R₄₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₅; R₂₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl; R₃₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl; R₄₁₂ is hydrogen, alkyl or aryl, provided, R₄₁₂ is other than phenyl; R₄₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl; and wherein either R₁ is hydroxyl, and/or at least one of R₂, R₃, or R₄ is hydroxyl, —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁₂, —OC(O)NHR₄₁₃, or —OSO₂R₄₁₄.

A further aspect of the invention is a compound corresponding to Formula 703

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, R₁₃, R₁₇, R₁₁₁, R₂₁₁, R₂₁₃, R₂₁₂, R₂₁₄, R₃₁₁, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₁, R₄₁₃, R₄₁₄, R₅₁₁, and R₁₂₁, are as defined above in connection with Formulae 600 and 700; R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than methyl or phenyl; and wherein at least one of R₂, R₃, or R₄ is —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁2, —OC(O)NHR₄₁₃, or —OSO₂R₄₁₄.

Other objects and features will be in part apparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to an improved synthetic method for preparing optically active hexahydroisoquinolines. Among the various aspects of the present invention is the preparation of various hexahydroisoquinolines (Formula 800) from the stepwise reduction of particular dihydroisoquinolines (Formulae 600 and 601). For example, in some of the various embodiments, a dihydroisoquinoline is reduced in the presence of a hydrogen source, an asymmetric catalyst, and, optionally, silver tetrafluoroborate to produce an optically active tetrahydroisoquinoline (Formulae 700, 701, and 702). The optically active tetrahydroisoquinoline can subsequently undergo a Birch reduction by contact with a reducing agent to form a hexahydroisoquinoline (Formula 800) without loss of optical activity. Various dihydroisoquinolines (Formula 601) and tetrahydroisoquinolines (Formulae 701 and 702) of the invention are substituted with ester, amide, or sulfonate ester protecting groups in order to facilitate reaction and isolation of intermediates.

Generally, the processes for the synthetic transformations of the invention described above are depicted in Reaction Scheme 1 below.

Each of these compounds and synthetic steps are described in more detail below.

Hexahydrolsoquinolines

As described above for Reaction Scheme 1, an aspect of the present invention is a process for preparing hexahydroisoquinolines corresponding to Formula 800

wherein

R₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₁₁₁;

R₅, R₆, R₇, and R₁₃ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₁₂₁:

R₁₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₁₂₁;

R₁₇ is hydrogen or acyl;

R₂₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₅;

R₃₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₅;

R₄₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₅;

R₁₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl;

R₁₂₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl;

R₂₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl;

R₃₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl;

R₄₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl;

R₅₁₂ is hydrocarbyl, or substituted hydrocarbyl; and

wherein at least one of R₁, R₂₁, R₃₁, or R₄₁ is hydroxyl.

Although R₂₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₅, in some of the various embodiments, R₂₁ is hydrogen or —OR₂₁₅. In some of these embodiments, R₂₁₅ is hydrogen, alkyl, or aryl. Preferably, R₂₁₅ is hydrogen or alkyl. More preferably, R₂₁₅ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl. In some of the various embodiments, R₂₁₅ is hydrogen, methyl, or phenyl.

Similarly, although R₃₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₅, in some embodiments, R₃₁ is hydrogen or —OR₃₁₅. In some of these embodiments, R₃₁₆ is hydrogen, alkyl, or aryl. Preferably, R₃₁₅ is hydrogen or alkyl. More preferably, R₃₁₅ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl. In some of the various embodiments, R₃₁₅ is hydrogen, methyl, or phenyl.

As noted above, R₄₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₅, in some embodiments, R₄₁ is hydrogen or —OR₄₁₅. In some of these embodiments, R₄₁₅ is hydrogen, alkyl or aryl. More preferably, R₄₁₅ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl. In some of the various embodiments, R₄₁₅ is hydrogen, methyl, or phenyl.

Further, R₆ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₅₁₁, in some embodiments, R₆ is hydrogen or —OR₅₁₁. In some of these embodiments, R₅₁₁ is hydrogen, alkyl, or aryl. Preferably, R₅₁₁ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl; more preferably, methyl.

As noted above, R₁₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₁₂₁, in some embodiments, R₁₂ is hydrogen, alkyl, alkenyl, aryl, aralkyl, or halo. Preferably, R₁₂ is hydrogen, alkyl, allyl, benzyl, or halo.

In many of the various embodiments, R₁, R₅, R₇, and R₁₃ are hydrogen.

In combination, among the preferred embodiments are hexahydroisoquinolines corresponding to Formula 800 wherein R₂₁ is hydrogen or —OR₂₁₅ wherein R₂₁₅ is hydrogen, alkyl, or aryl. In some embodiments, R₂₁5 is hydrogen or methyl. In these embodiments, R₃₁ is hydrogen or —OR₃₁₅. In various preferred embodiments, R₃₁₅ is hydrogen, alkyl, or aryl, preferably, R₃₁₅ is hydrogen or alkyl. In some of these embodiments, R₃₁₅ is hydrogen or methyl. Further, R₄₁ is hydrogen or —OR₄₁₅. In various embodiments, R₄₁₅ is hydrogen, alkyl, or aryl, preferably, R₄₁₅ is hydrogen or alkyl. In some embodiments, R₄₁₅ is hydrogen or methyl. Further yet, R₆ is hydrogen or —OR₅₁₁. In some of these embodiments, R₅₁₁ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl; preferably, hydrogen or methyl. Additionally, R₁₂ is hydrogen, alkyl, allyl, benzyl, or halo. In many of these embodiments, R₁, R₅, R₇, and R₁₃ are hydrogen.

Tetrahydrolsoquinolines

As described in Reaction Scheme 1, a tetrahydroisoquinoline corresponding to Formula 700 has the structure

wherein

R₁ and R₇ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₁₁₁;

R₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₁;

R₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₁;

R₄ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₁;

R₅ and R₆ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₅₁₁;

R₁₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₁₂₁;

R₁₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₅₁₁;

R₁₇ is hydrogen or acyl;

R₁₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl;

R₂₁₁ is hydrogen, hydrocarbyl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄;

R₂₁₂, R₂₁₃, and R₂₁₄ are independently hydrocarbyl or substituted hydrocarbyl;

R₃₁₁ is hydrogen, hydrocarbyl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄;

R₃₁₂, R₃₁₃, and R₃₁₄ are independently hydrocarbyl or substituted hydrocarbyl;

R₄₁₁, is hydrogen, hydrocarbyl, —C(O)R₄₁₂, —C(O)NHR₄₁₃, or —SO₂R₄₁₄;

R₄₁₂, R₄₁₃, and R₄₁₄ are independently hydrocarbyl or substituted hydrocarbyl;

R₅₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl;

R₁₂₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and

wherein at least one of R₁, R₂, R₃, or R₄ is hydroxyl, or at least one of R₂, R₃, or R₄ is —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, or —OSO₂R₂₁₄.

In various embodiments, the tetrahydroisoquinoline structure corresponds to Formula 701 wherein R₁, R₂, R₃, R₄, R₅, R₅, R₇, R₁₂, R₁₃, R₁₁₁, R₂₁₁, R₂₁₃, R₂₁₄, R₃₁₁, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₁, R₄₁₂, R₄₁₃, R₄₁₄, R₅₁₁, and R₁₂₁ are defined as above for Formula 700; wherein at least one of R₂, R₃, or R₄ is —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁₂, —OC(O)NHR₄₁₃, or —OSO₂R₄₁₄; and R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than methyl.

In some embodiments, the tetrahydroisoquinoline structure corresponds to Formula 702 wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, R₁₃, R₁₁₁, R₂₁₁, R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₁, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₁, R₄₁₃, R₄₁₄, R₅₁₁, and R₁₂₁ are defined as above for Formula 700; wherein at least one of R₂, R₃, or R₄ is —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁₂, —OC(O)NHR₄₁₃, or —OSO₂R₄₁₄; and R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than phenyl.

In other embodiments, the tetrahydroisoquinoline structure corresponds to Formula 703 wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, R₁₃, R₁₁₁, R₂₁₁, R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₁, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₁, R₄₁₃, R₄₁₄, R₅₁₁, and R₁₂₁ are defined as above for Formula 700; wherein at least one of R₂, R₃, or R₄ is —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁₂, —OC(O)NHR₄₁₃, or —OSO₂R₄₁₄; and R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than methyl or phenyl.

In some of the embodiments, the tetrahydroisoquinoline structure corresponds to Formula 704 wherein R₁, R₂₁, R₃₁, R₄₁, R₅, R₆, R₇, R₁₂, R₁₃, R₁₁₁, R₂₁₁, R₂₁₃, R₂₁₄, R₃₁₁, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₁, R₄₁₂, R₄₁₃, R₄₁₄, R₅₁₂, and R₁₂₁ are defined as above for Formula 800 and wherein at least one of R₁, R₂₁, R₃₁, or R₄₁ is hydroxyl.

Although R₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₁, in some of the various embodiments, R₂ is hydrogen or —OR₂₁₁. In some of these embodiments, R₂₁₁ is hydrogen, alkyl, aryl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄. Preferably, R₂₁₁ is hydrogen, alkyl, or —C(O)R₂₁₂ wherein R₂₁₂ is alkyl or aryl. More preferably, R₂₁₁ is —C(O)R₂₁₂ wherein R₂₁₂ is methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl. In some of the various embodiments, R₂₁₁ is —C(O)R₂₁₂ wherein R₂₁₂ is ethyl, propyl, butyl, pentyl, or hexyl.

Similarly, although R₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₁, in some embodiments, R₃ is hydrogen or —OR₃₁₁. In some of these embodiments, R₃₁₁ is hydrogen, alkyl, aryl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄. Preferably, R₃₁₁ is hydrogen, alkyl, or —C(O)R₃₁₂ wherein R₃₁₂ is alkyl or aryl. More preferably, R₃₁₁ is —C(O)R₃₁₂ wherein R₃₁₂ is methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl. In some of the various embodiments, R₃₁₁ is —C(O)R₃₁₂ wherein R₃₁₂ is ethyl, propyl, butyl, pentyl, or hexyl.

As noted above, R₄ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₁, in some embodiments, R₄ is hydrogen or —OR₄₁₁. In some of these embodiments, R₄₁₁ is hydrogen, alkyl, aryl, —C(O)R₄₁₂, —C(O)NHR₄₁₃, or —SO₂R₄₁₄. Preferably, R₄₁₁ is hydrogen, alkyl, or —C(O)R₄₁₂ wherein R₄₁₂ is alkyl or aryl. More preferably, R₄₁₁ is —C(O)R₄₁₂ wherein R₄₁₂ is ethyl, propyl, butyl, pentyl, or hexyl.

Further, R₆ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₅₁₁, in some embodiments, R₆ is hydrogen or —OR₅₁₁. In some of these embodiments, R₅₁₁ is hydrogen, alkyl, or aryl. Preferably, R₅₁₁ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl; more preferably, methyl.

As noted above, R₁₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₁₂₁, in some embodiments, R₁₂ is hydrogen, alkyl, alkenyl, aryl, aralkyl, or halo. Preferably, R₁₂ is hydrogen, alkyl, allyl, benzyl, or halo.

In many of the various embodiments, R₁, R₅, R₇, and R₁₃ are hydrogen.

In combination, among the preferred embodiments are tetrahydroisoquinolines corresponding to Formulae 700, 701, 702, and 703 wherein R₂ is hydrogen or —OR₂₁₁ wherein R₂₁₁ is hydrogen, alkyl, or —C(O)R₂₁₂ wherein R₂₁₂ is alkyl or aryl. In some embodiments, R₂₁₂ is ethyl, propyl, butyl, pentyl, or hexyl. In these embodiments, R₃₁₁ is hydrogen or —OR₃₁₁. In various preferred embodiments, R₃₁₁ is hydrogen, alkyl, aryl, or —C(O)R₃₁₂, preferably, R₃₁₁ is hydrogen, alkyl, or —C(O)R₃₁₂ wherein R₃₁₂ is alkyl or aryl. In some of these embodiments, R₃₁₂ is ethyl, propyl, butyl, pentyl, or hexyl. Further, R₄ is hydrogen or —OR₄₁₁. In various embodiments, R₄₁₁ is hydrogen, alkyl, aryl, or —C(O)R₄₁₂, preferably, R₄₁₁ is hydrogen, alkyl, or —C(O)R₄₁₂ wherein R₄₁₂ is alkyl or aryl. In some embodiments, R₄₁₂ is methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl. Alternatively, R₄₁₂ is ethyl, propyl, butyl, pentyl, or hexyl. Further yet, R₆ is hydrogen or —OR₅₁₁. In some of these embodiments, R₅₁₁ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl; preferably, methyl. Additionally, R₁₂ is hydrogen, alkyl, allyl, benzyl, or halo. In many of these embodiments, R₁, R₅, R₇, and R₁₃ are hydrogen.

Dihydroisoquinolines

As described above for Reaction Scheme 1, a 3,4-dihydroisoquinoline corresponding to Formula 600 has the structure

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, and R₁₃ are defined as above in connection with Formula 700.

In various embodiments, the dihydroisoquinoline structure corresponds to Formula 601 wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, R₁₃, R₁₁₁, R₂₁₁, R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₁, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₁, R₄₁₃, R₄₁₄, R₅₁₁ and R₁₂₁ are defined as above for Formula 600; wherein at least one of R₂, R₃, or R₄ is —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁₂, —OC(O)NHR₄₁₃, or —OSO₂R₄₁₄; and R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than methyl.

Preferred substituent groups and preferred combinations of substituent groups for R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₂, and R₁₃ are detailed above in connection with Formula 700.

Generally, compounds of Formulae 600 and 601 can be prepared by methods described by Rice in U.S. Pat. No. 4,521,601, herein incorporated by reference. Further, these compounds can be prepared by methods described by Kashdan et al. (J. Org. Chem. 1982, 47 2638-2643) and by Beyerman et al. (J. Royal Netherlands Chem. Soc. 1978, 97(5), 127-130), and by copending application U.S. Application Ser. No. 60/874,131 (Attorney Docket No. H-MP-00021), herein incorporated by reference.

Asymmetric Reduction of a 3,4-Dihydroisoquinoline to a Tetrahydroisoquinoline

For the process of the present invention, the structures of the products (e.g., hexahydroisoquinolines), reactants (e.g., 3,4-dihydroisoquinolines) and intermediates (e.g., tetrahydroisoquinolines) are described above. The first step of this process comprises a reduction of the imine moiety in a 3,4-dihydroisoquinoline to produce a tetrahydroisoquinoline. This imine reduction reaction mixture typically contains the 3,4-dihydroisoquinoline, the asymmetric catalyst, and a hydrogen source. The imine reduction reaction mixture can optionally contain silver tetrafluoroborate.

This imine reduction reaction forms another chiral center in the tetrahydroisoquinoline, and thus, preferably, occurs in an asymmetric environment. In various embodiments, the process of the invention uses an asymmetric catalyst to provide an asymmetric environment for the reduction of the imine moiety. The asymmetric catalyst comprises a metal or metal source and a chiral ligand. The metal or metal source is selected from ruthenium, a ruthenium complex, osmium, an osmium complex, rhodium, a rhodium complex, iridium, iridium complex, and combinations thereof. The chiral ligand can have the structure of formulae 670 or 680

wherein R₆₇₁, R₆₇₂, and R₆₇₃ are independently alkyl or aryl and wherein R₆₈₁ is alkyl or aryl.

In various preferred embodiments, the chiral ligand can have the structure of 670 wherein R₆₇₂ and R₆₇₃ are phenyl and R₆₇₁ is aryl. In some of these embodiments, R₆₇₁ can be tolyl, mesityl, or naphthyl. In various preferred embodiments, the chiral ligand can be (1S,2S)-(+)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine or (1R,2R)-(−)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine, depending on which enantiomer is the desired product. In other embodiments, the chiral ligand can have the structure of 680 wherein R₆₈₁ is tolyl, mesityl, 2,4,6-triisopropylphenyl, or naphthyl. In particular embodiments, R₆$1 can be p-tolyl, 2,4,6-triisopropylphenyl, 1-naphthyl, or 2-naphthyl.

In various preferred embodiments, the asymmetric catalyst comprises a ruthenium source comprising dichloro(p-cymene) ruthenium (11) dimer and a chiral ligand comprising (1S,2S)-(+)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine. Typically, about 0.005 g to about 0.015 g of asymmetric catalyst per gram of starting 3,4-dihydroisoquinoline is present in the imine reduction reaction mixture.

The rate of the imine reduction reaction is directly proportional to the concentration of asymmetric catalyst (e.g., metal or metal source and chiral ligand) used. For example, an imine reduction reaction mixture that contains a greater amount of asymmetric catalyst has a shorter reaction time than a reaction mixture that contains a smaller amount of asymmetric catalyst.

In some of the embodiments, the hydrogen source for the imine reduction comprises protic compounds (including alcohol and formic acid). Preferably, the hydrogen source is a protic compound comprising a carboxylic acid. Particularly, the hydrogen source comprises a formic acid-triethylamine azeotropic mixture of salts; preferably, this mixture has a ratio of formic acid to triethyl amine of about 5:2. About 3 equivalents to about 3.5 equivalents of triethylamine and about 7.5 equivalents to about 8 equivalents of formic acid are used for each equivalent of 3,4-dihydroisoquinoline.

In various preferred embodiments, the reaction mixture can contain silver tetrafluoroborate. Typically, the silver tetrafluoroborate is present in similar amounts as the asymmetric catalyst and typically, ranges from about 0.005 g to about 0.015 g of silver tetrafluoroborate per gram of starting 3,4-dihydroisoquinoline present in the imine reduction reaction mixture. The addition of silver tetrafluoroborate increases the reaction rate. For example, the reaction time for the reduction in the presence of silver tetrafluoroborate is about 30% to about 50% shorter than the reaction time for the reduction in the absence of silver tetrafluoroborate.

Upon addition of the formic acid and triethylamine to the reaction mixture, there is an exotherm; this exotherm is followed by cooling of the reaction mixture and addition of the 3,4-dihydroisoquinoline and the asymmetric catalyst. The imine reduction occurs at a temperature of from about 10° C. to about 40° C.; preferably, from about 20° C. to about 30° C.; more preferably, from about 24° C. to about 26° C. The imine reduction reaction mixture is allowed to react for about 4 hours to about 24 hours; preferably for about 18 hours.

The imine reduction reaction mixture typically includes an aprotic, polar solvent. This solvent can be selected from acetonitrile, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), halocarbons (e.g., dichloromethane, chloroform), dimethylformamide (DMF), dimethylacetamide (DMAC), N-methylpyrrolidinone (NMP), and combinations thereof. Preferably, the solvent comprises acetonitrile.

Upon completion of the imine reduction, the product tetrahydroisoquinoline precipitates from the solution and can be isolated by methods known in the art. For example, the product can be collected by filtration of the reaction mixture followed by washing the product solid with the solvent.

Birch Reduction of a Tetrahydroisoquinoline to a Hexahydroisoquinoline

The second step of the process of the invention is a Birch reduction of a tetrahydroisoquinoline (Formulae 700, 701, 702, and 703) to form a hexahydroisoquinoline (Formula 800). The Birch reduction is generally effected using a reducing agent. Thus, the Birch reduction reaction mixture comprises a tetrahydroisoquinoline and a reducing agent. Exemplary reducing agents comprise an alkali metal and at least one of liquid ammonia, methylamine, ethylamine, ethylenediamine, and combinations thereof. Preferably, the reducing agent for the Birch reduction comprises lithium metal and liquid ammonia. In alternative embodiments, the reducing agent comprises lithium metal, sodium metal, potassium metal, or calcium metal and methylamine or ethylamine.

The Birch reduction reaction mixture typically also includes a solvent mixture. This solvent mixture comprises isopropyl alcohol (IPA), t-butyl alcohol, tetrahydrofuran (THF), ammonia, and combinations thereof. Preferably, the solvent comprises IPA, THF, and ammonia; and, in some embodiments, the ratio of IPA to THF to liquid ammonia is 1 to 2 to 3. Depending on the reagents used, the Birch reduction occurs at a temperature of from about −80° C. to about 10° C. When liquid ammonia is used as a reagent, the reduction takes place at about −80° C. to about −35° C. When methylamine or ethylamine is used as a reagent, the reduction takes place at a temperature from about −10° C. to about 10° C. The Birch reduction reaction mixture is maintained at the above temperatures for about 10 minutes to about 4 hours.

Typically, the tetrahydroisoquinoline was suspended or dissolved in a cosolvent such as tetrahydrofuran ort-butyl alcohol. This mixture was cooled to −10° C. and methylamine was added and the temperature was maintained at −10° C. The lithium metal was charged in portions and the reaction mixture was stirred at −10° C. for another 30 minutes to about 2 hours after sufficient lithium metal was charged. The reaction mixture was warmed to room temperature and then added to water to produce the product hexahydroisoquinoline as a precipitate.

Uses of Intermediates

The above-described synthesis stages are important in the preparation of morphinans and analogs thereof. General reaction schemes for the preparation of morphinans are disclosed in U.S. Pat. No. 4,368,326 to Rice, the entire disclosure of which is incorporated by reference. The morphinans and analogs thereof (i.e., the morphinans contain an X group of N—(R₁₇) or N+-(R_(17a)R_(17b))) of interest in the practice of the present invention are opiate receptor agonists or antagonists and generally are compounds corresponding to Formula (24)

wherein -A₆-A₇-A₈-A₁₄- corresponds to Formulae (S), (T), (U), (V), (W), (X), (Y), or (Z):

R₁₁ and R₂₂ are independently hydrogen, substituted and unsubstituted acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxy, protected hydroxy, or nitro;

R₁₄ is hydrogen, acyloxy, hydroxy, or protected hydroxy;

R₁₇ is hydrogen, alkyl, alkoxy, alkylenecycloalkyl, allyl, alkenyl, acyl, formyl, formyl ester, formamide, or benzyl;

R_(17a) and R_(17b) are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, or benzyl;

R₁₈ and R₁₉ are independently hydrogen, substituted and unsubstituted acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, arylthio, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxy, or nitro, or R₁₈ and R₁₉ together form keto:

R₃₃ is alkoxy, acyloxy, hydroxy, or protected hydroxy;

R₆₁ is alkoxy, acyloxy, hydroxy, or protected hydroxy;

R₆₂ and R₆₃ are independently hydrogen, alkyl, alkenyl, alkynyl, allyl, alkoxy, alkylthio, acyloxy, or aryl, together form keto, or together with the carbon atom to which they are attached form a ketal, dithioketal, or monoketal;

R₇₁ and R₈₁ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or halo; and

X is oxygen, sulfur, —S(O)—, —S(O₂)—, —C(R₁₈)(R₁₉)—, —N(R₁₇)—, or —N⁺(R_(17a)R_(17b))-.

In a particular embodiment, the products and intermediates produced according to the present invention are useful in the preparation of a morphinan compound corresponding to Formula (24) wherein X is —N(R₁₇)— and R₁₇ is defined as above.

For purposes of clarity, the carbon atoms of Formulae (S), (T), (U), (V), (W), (X), (Y), and (Z) corresponding to A₆, A₇, A₈, and A₁₄ of Formula (24), respectively, have been identified (by indicating with an arrow which carbon atom corresponds to each). Further, squiggly lines have been included in Formulae (S), (T), (U), (V), (W), (X), (Y), and (Z) to indicate the points of attachment to the polycyclic ring of Formula (24).

Exemplary morphinans that may be produced according to a variety of methods include, for instance, nordihydrocodeinone (i.e., Formula (24) wherein R₁₁, R₁₇, and R₂₂ are hydrogen, R₃₃ is methoxy, X is —N(R₁₇)—, and -A₆-A₇-A₈-A₁₄- corresponds to Formula (Y) wherein R₁₄ is hydrogen, R₆₂ and R₆₃ together form keto, and R₇₁ and R₈₁ are hydrogen) (which corresponds to Formula (241) below); dihydrocodeinone (i.e., Formula (24) wherein R₁₁, and R₂₂ are hydrogen, R₁₇ is methyl, R₃₃ is methoxy, X is —N(R₁₇)—, and -A₆-A₇-A₈-A₁₄- corresponds to Formula (Y) wherein R₁₄ is hydrogen, R₆₂ and R₆₃ together form keto, and R₇₁ and R₈₁ are hydrogen) (which corresponds to Formula (242) below); noroxymorphone (i.e., Formula (24) wherein R₁₁, R₁₇, and R₂₂ are hydrogen, R₃₃ is hydroxy, X is —N(R₁₇)—, and -A₆-A₇-A₈-A₁₄- corresponds to Formula (Y) wherein R₁₄ is hydroxy, R₆₂ and R₆₃ together form keto, and R₇₁ and R₈₁ are hydrogen) (which corresponds to Formula (243) below); and salts, intermediates, and analogs thereof.

DEFINITIONS

The term “acyl,” as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R₁, R₁O—, R₁R₂N—, or R₁S—, R₁ is hydrocarbyl, heterosubstituted hydrocarbyl, substituted hydrocarbyl, or heterocyclo, and R₂ is hydrogen, hydrocarbyl or substituted hydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (O), e.g., RC(O)O— wherein R is as defined in connection with the term “acyl.”

The term “alkyl” as used herein describes groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.

The term “alkenyl” as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.

The term “alkynyl” as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.

The term “aromatic” as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic aromatic groups. These aromatic groups are preferably monocyclic, bicyclic, or tricyclic groups containing from 6 to 14 atoms in the ring portion. The term “aromatic” encompasses the “aryl” and “heteroaryl” groups defined below.

The term “aryl” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The terms “heterocyclo” or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo groups include heteroaromatics as described below. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano, ketals, acetals, esters and ethers.

The term “heteroaryl” as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaryl group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon. Exemplary heteroaryls include furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano, ketals, acetals, esters and ethers.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, aryloxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals, acetals, esters and ethers.

Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.

EXAMPLES

The following non-limiting examples are provided to further illustrate the present invention.

Example 1 Preparation of Compound 711 from Compound 611 and Compound 712 from Compound 612

To a 5 L dried reactor under inert atmosphere, was added acetonitrile (1.4 L, anhydrous). To the acetonitrile, triethylamine (455.8 g, 4.5 moles) was introduced. The reaction flask was chilled to 5° C. 98% Formic acid (548.1, 8.75 moles) was added dropwise while maintaining the temperature below 30° C. After the formic acid was added, the formed salt solution was degassed for 1 hour. Compound 610 (434.5, 1.36 moles) was added all at once followed by 3.0 g dichloro(p-cymene) ruthenium (II) dimer and 3.0 g of (1S,2S)-(+)-N-4-toluenesulfonyl)-1,2-diphenylethylene-1,2-diamine. When Compound 610 was used as the starting material, an additional 1.0 equivalent of 98% formic acid was added to convert the Na salt to the phenol in situ. The reaction initially turned green, then slowly changed to yellow. The reaction mixture was stirred for 16 hours at room temperature. HPLC indicated the reaction was complete. The product, Compound 711 (460 g, 97.9% yield, 97.3% assay, 99% e.e. (R)), was isolated by filtering the solid and washing it with acetonitrile (500 mL) followed by drying overnight (40° C., 30 in Hg). Typically, the yields of this reaction were 95% and the enantiomeric excess was 95% R. When (1R,2R)-(−)-N-4-toluenesulfonyl)-1,2-diphenylethylene-1,2-diamine was substituted for (1S,2S)-(+)-N-4-toluenesulfonyl)-1,2-diphenylethylene-1,2-di amine in this process the S-enantiomer of Compound 711 was produced.

To produce Compound 711 in high enantiomeric purity, a general ratio of the reactants must be maintained. For example, a ratio of about 2 equivalents of triethylamine to 5 equivalents of formic acid is desired. Thus, generally, a ratio of about 3.2 to 3.3 equivalents of triethylamine to 7.8 to 7.9 equivalents of 98% formic acid was used. Typically, about 0.5 wt % to 1.5 wt % of Ru catalyst and chiral ligand was used. The reaction time directly depends on the catalyst and ligand loading; for example, lower catalyst and ligand loading results in a longer reaction time.

Example 2 Preparation of Compound 811 from Compound 711

To a 5 L dried reaction flask was added Compound 711 (392.5 g, 1.14 moles), isopropyl alcohol (500 mL, anhydrous), and tetrahydrofuran (1.0 L, anhydrous, inhibitor free). The obtained slurry was cooled to −60° C. Anhydrous ammonia (approximately 1.5 L) was condensed into the slurry. The mixture was stirred for 30 minutes while maintaining the temperature at −60° C. Then, lithium metal (30.2 g, 4.35 moles) was added to the reaction mixture in 5 portions over an hour period. After the last addition, the color of the reaction was blue. HPLC analysis indicated the reaction was complete. Then, anhydrous methanol (400 mL) was added dropwise. After the addition was complete, the reaction mixture was slowly warmed to room temperature (approximately 8 hours with good stirring) allowing excess ammonia to evaporate. Distilled water (750 mL) was added to the mixture. After stirring for 30 minutes, glacial acetic acid was added slowly to a pH of 9.5 to 10. After stirring for 1 hour, the product, Compound 811 (330.1 g, 96% yield, 98.6% e.e. (R)), was isolated by filtration after washing the solid with distilled water (1.0 L) and drying under vacuum (30C, 30 in Hg, 48 hours).

Generally, the solvent ratio of isopropyl alcohol (IPA) to tetrahydrofuran (THF-anhydrous) to liquid ammonia is about 1 to 2 to 3. Depending on the activity of the lithium metal about 1 to 30 equivalents are used. The lithium metal was added until electron transfer (blue color) was observed.

Example 3 Preparation of Compound 711 from Compound 611

Triethylamine (1.06 g per gram of Compound 611) and acetonitrile (6 mL per gram of Compound 611) were added to a reactor equipped with a mechanical stirrer. Formic acid (1.2 g per gram of Compound 611) was added in four portions to the reactor resulting in an exotherm. The reaction temperature was controlled below 80° C. during the addition. After cooling to room temperature, a solution of 5 equivalents formic acid to 2 equivalents triethylamine in acetonitrile was formed. Compound 611 was added to form a suspension. It was flushed with nitrogen for 15 min and the Ru catalyst 111 described below (0.01 g per gram of Compound 611) was added. The suspension was again flushed with nitrogen for 15 minutes and stirred at room temperature for 10 hours. The end point of the reaction was determined by HPLC (Compounds 711:611 were >99:1). The mixture was diluted with water (9 mL per gram of Compound 611) until dissolved. To the solution, 28% ammonium hydroxide (1.0 mL per gram of Compound 611) was added to give a precipitate. The pH of the mixture was further adjusted with ammonium hydroxide (28%) to about 9.3-9.7. The resulting suspension was filtered and the solid obtained was washed with water (3×1.0 mL per gram of Compound 611) and dried under vacuum (20 inches) and flowing nitrogen at 60° C. for 20 hours to give the product as an off-white solid. Yields ranged from 80% to 95% and R:S ratio was 95:5 (90% e.e.).

Example 4 Preparation of Compound 711 from Compound 611

Table 1 shows that the results for the catalytic asymmetric reduction of Compound 611 to Compound 7111 The reaction was carried out in either acetonitrile (CH₃CN) or methylene chloride (CH₂Cl₂) at room temperature using from 0.5 mol % to 2 mol % catalyst loading. Excess formic acid-triethylamine (5:2) was used as the reducing reagent. The catalyst was prepared by combining equal amounts of (1S,2S)-(+)-N-4-Page 18 of 28 toluenesulfonyl)-1,2-diphenylethylene-1,2-diamine and either dichloro(p-cymene) ruthenium (11) dimer (catalyst 111), dichloro(benzene) ruthenium (II) dimer (catalyst 112), or dichloro(mesitylene) ruthenium (II) dimer (catalyst 114). The yields and enantioselectivity resulting from the asymmetric reduction are listed in table 1.

TABLE 1 Asymmetric reduction of imine Compound 611 to amine Compound 711. reaction Catalyst Solvent Catalyst:substrate time (h) Yield (%) Ratio of R:S 112 CH₃CN 1:100 16 47 90:10 112 CH₂Cl₂ 1:100 16 89 89:11 111 CH₂Cl₂ 1:100 16 88 96:4  111 CH₃CN 1:100 16 94 100:0  111 CH₂Cl₂ 1:200 16 92 100.0:0    111 CH₂Cl₂ 1:50  16 94 98.5:1.5  114 CH₂Cl₂ 1:100 16 92 48.5:51.5

Example 5 Preparation of Compound 711 from Compound 613

The results in Table 2 show that Compound 613 (the salt of Compound 611) can be directly reduced to Compound 711 using the reaction conditions of Table 1 with excess base. The reactions of Table 2 were carried out in acetonitrile with Compound 611 (1.68 mmol), 5:2 formic acid-triethylamine (10.8 mmol), and 1 mol % Ru catalyst 111.

TABLE 2 Asymmetric reduction of Compound 613 conversion H₃PO₄ NaOAc NaHCO₃ NaCl 611/613/ mmol mmol mmol NEt₃ mmol mmol time (h) 711R/711S 711R/711S 3.36 15 62/11/19/3 6.72 15 78/19/3/0 13.4 15 83/15/1/0 6.72 65 86/11/2/0 6.72 6.72 65 2/5/85/3 97/3 6.72 13.4 65 1/3/93/3 97/3 65 1/2/93/3 97/3 6.72 6.72 6.72 15 26/2/61/9 87/13 6.72 6.72 6.72 15 66/6/19/6 75/25 6.72 6.72 38 1/2/86/7 92/8 6.72 13.4 38 0.1/1.6/88/6 93/67 6.72 15 0.6/3/92/3 97/3 13.4 15 0.6/3/92/3 97/3

Example 6 Preparation of Compound 713 from Compound 611

Triethylamine (1.06 g per gram of Compound 611) and acetonitrile (6 mL per gram of Compound 611) were added to a reactor equipped with mechanical stirrer. Formic acid (1.2 g per gram of Compound 611) was added in four portions to the reactor. The exothermic reaction temperature was controlled at below 80° C. during the addition of formic acid. The reaction mixture was cooled to room temperature to form a solution of formic acid-triethylamine (5:2) in acetonitrile. Compound 611 was added to the solution to form a suspension. After flushing with nitrogen for 15 minutes, the Ru catalyst 111 (0.01 g per gram of Compound 611) was added. The suspension was again flushed with nitrogen for 15 minutes and stirred at room temperature for 10 hours. The reaction mixture was heated to 100° C. for 2 hours to form Compound 713; Compound 713 has a formyl group attached to the nitrogen. Compound 713 was isolated as a solid by pouring the solution into an ice cold ammonium hydroxide solution (20 mL per gram of Compound 611).

Example 7 Preparation of Compound 811 from Compound 711

To a reactor, isopropyl alcohol (IPA) (2.0 mL/g of Compound 711), tetrahydrofuran (THF) (4.0 mL/g of Compound 711) and the Compound 711 (pre-dried to the limit of detection (LOD) or <0.2% water) were added. The suspension was cooled to −55° C. with stirring in a dry-ice bath. Liquid ammonia (10 mL/g of Compound 711) was condensed into the reactor at −55° C. The reaction mixture was cooled at −55° C. and was flushed with nitrogen for 15 minutes. Sodium t-butoxide (NaOt-Bu) (0.35 g/g of Compound 711) was added and stirred for another 15 minutes. Lithium (cut, 0.070 g/g of Compound 711) was added in three portions to the mixture (⅓×0.070 g/g of Compound 711 in each portion) and the temperature of the reaction mixture was maintained at −45 to −55° C. by using a dry-ice bath and by controlling the addition rate. The reaction mixture was stirred for 50 minutes until all of the lithium was added. If the blue color of the reaction mixture lasted for more than 30 minutes the reaction was complete; otherwise, more lithium was added until the blue color persisted for 30 minutes. Methanol (1.0 g/g of Compound 711) was added after the reaction was determined to be complete. The reaction mixture was warmed from −28° C. to 20° C. to remove most of the ammonia and then stirred for another 1 hour after the temperature reached 20° C. Water was degassed by bubbling nitrogen through it for 20 minutes and this degassed water (10 mL/g of Compound 711) was added under nitrogen to the above mixture. The suspension was stirred for 30 minutes (pH=12.4) to form a solution. A solution of aqueous acetic acid (acetic acid at 0.95 ml/g of Compound 711 and H₂O at 1.90 mL/g of Compound 711) was added to form a suspension (pH 7.8). The suspension's pH was adjusted to 8.8 to 9.2 with 28% ammonium hydroxide (˜0.25 mL/g of Compound 711). The suspension was stirred for 1 hour and filtered. The reactor was repeatedly rinsed with water (3.0 mL/g of Compound 711) which was then used to wash the solid filtrate. The solid was further washed with water (3.0 mL/g of Compound 711) and dried under flowing air for 4 h and then dried under vacuum (20 inches) at 60° C. for 20 hours to give the product as an off-white solid in about 90% yield.

Example 8 Preparation of Compound 811 and 815 from Compound 711

In order to carry out the Birch reduction at higher temperature, the low boiling point reagent, ammonia, was replaced with higher boiling point reagents; for example, methylamine, ethylamine, or ethylenediamine. It was found that both methylamine and ethylamine could be used as electron transfer reagents to give the desired product at −10° C. to 10° C. When Li/NH₂Me/THF/t-BuOH was used for the reduction of Compound 711, 80% yield of Compound 811 was obtained as a solid. When Li/NH₂Et/THF/t-BuOH was used for the reduction of Compound 711, Compound 811 was formed in 50% to 70% yield. The reaction of Compound 711 in the system of Li/NH₂CH₂CH₂NH₂/THF under reflux formed undesired Compound 815.

When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense. 

1. A process for the preparation of a hexahydroisoquinoline corresponding to Formula 800, the process comprising reducing a tetrahydroisoquinoline corresponding to Formula 704:

wherein R₁ and R₇ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₁₁₁; R₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₁; R₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₁; R₄ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₁; R₅ and R₆ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₅₁₁; R₁₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR_(121;) R₁₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₅₁₁; R₁₇ is hydrogen, or acyl; R₂₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₅; R₃₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₆; R₄₁ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₅; R₁₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; R₂₁₁ is hydrogen, hydrocarbyl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄; R₂₁₂, R₂₁₃ and R₂₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₂₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl; R₃₁₁ is hydrogen, hydrocarbyl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄; R₃₁₂, R₃₁₃, or R₃₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₃₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl; R₄₁₁ is hydrogen, hydrocarbyl, —C(O)R₄₁₂, —C(O)NHR₄₁₃, or —SO₂R₄₁₄; R₄₁₂ is hydrogen, alkyl or aryl, provided, R₄₁₂ is other than phenyl; R₄₁₃, and R₄₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₄₁₅ is hydrogen, hydrocarbyl or substituted hydrocarbyl; R₅₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and R₁₂₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; wherein either R₁ is hydroxyl, and/or at least one of R₂, R₃, or R₄ is hydroxyl, —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁₂, —OC(O)NHR₁₃, or —OSO₂R₄₁₄.
 2. The process of claim 1, wherein: R₂ is —OR₂₁₁; R₂₁₁ is hydrogen, alkyl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄; and R₂₁₂, R₂₁₃, and R₂₁₄ are independently alkyl or aryl.
 3. The process of claim 1, wherein: R₃ is —OR₃₁₁; R₃₁₁ is hydrogen, alkyl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄; and R₃₁₂, R₃₁₃, and R₃₁₄ are independently alkyl or aryl.
 4. The process of claim 1, wherein: R₄ is —OR₄₁₁; R₄₁₁ is hydrogen, alkyl, —C(O)R₄₁₂, —C(O)NHR₄₁₃, or —SO₂R₄₁₄; R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than phenyl; and R₄₁₃ and R₄₁₄ are independently alkyl or aryl.
 5. The process of claim 1, wherein R₁₂ is alkyl, allyl, benzyl, or halo.
 6. The process of claim 1, wherein R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₂, R₄₁₃, and R₄₁₄ are methyl.
 7. The process of claim 1, wherein: R₂ is —OR₂₁₁; R₂₁₁ is hydrogen, alkyl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄; and R₂₁₂, R₂₁₃, and R₂₁₄ are independently alkyl or aryl: R₃ is —OR₃₁₁; R₃₁₁ is hydrogen, alkyl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄; and R₃₁₂, R₃₁₃, and R₃₁₄ are independently alkyl or aryl; R₄ is —OR₄₁₁; R₄₁₁ is hydrogen, alkyl, —C(O)R₄₁₂, —C(O)NHR₄₁₃, or —SO₂R₄₁₄; R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than phenyl; and R₄₁₃ and R₄₁₄ are independently alkyl or aryl.
 8. The process of claim 7, wherein R₁₂ is alkyl, allyl, benzyl, or halo.
 9. The process of claim 7, wherein R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₂, R₄₁₃, and R₄₁₄ are methyl.
 10. The process of claim 7, wherein R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₂, R₄₁₃, and R₄₁₄ are methyl; R₃ is methoxy, R₄ is hydroxyl, —OC(O)CH₃, —OC(O)Ph, or —OSO₂CH₃, R₆ is methoxy, and R₁, R₂, R₅, R₇, R₁₂, and R₁₃ are hydrogen.
 11. The process of claim 1, wherein R₃ is methoxy, R₄ is hydroxyl, —OC(O)CH₃, —OC(O)Ph, or —OSO₂CH₃, R₆ is methoxy, and R₁, R₂, R₅, R₇, R₁₂, and R₁₃ are hydrogen.
 12. The process of claim 1, wherein a reducing agent reduces the tetrahydroisoquinoline to the hexahydroisoquinoline, the reducing agent comprising an alkali metal and/or an electron source.
 13. The process of claim 12, wherein the alkali metal is chosen from lithium, sodium and potassium and the electron source is chosen from liquid ammonia, methylamine, ethylamine, ethylenediamine, and combinations thereof.
 14. The process of claim 13, wherein the reducing agent comprises lithium and liquid ammonia.
 15. A compound corresponding to Formula 703:

wherein R₁ and R₇ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₁₁₁; R₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₂₁₁; R₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₃₁₁; R₄ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₄₁₁; R₅ and R₆ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR₅₁₁; R₁₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₁₂₁; R₁₃ is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR₅₁₁: R₁₇ is hydrogen, or acyl; R₁₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; R₂₁₁ is hydrogen, hydrocarbyl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄; R₂₁₂, R₂₁₃, and R₂₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₃₁₁ is hydrogen, hydrocarbyl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄; R₃₁₂, R₃₁₃, and R₃₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₄₁₁ is hydrogen, hydrocarbyl, —C(O)R₄₁₂, —C(O)NHR₄₁₃, or —SO₂R₄₁₄; R₄₁₂ is alkyl or aryl, provided, R₄₁₂ is other than methyl or phenyl; R₄₁₃, and R₄₁₄ are independently hydrocarbyl or substituted hydrocarbyl; R₅₁₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; R₁₂₁ is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and wherein at least one of R₂, R₃, or R₄ is —OC(O)R₂₁₂, —OC(O)NHR₂₁₃, —OSO₂R₂₁₄, —OC(O)R₃₁₂, —OC(O)NHR₃₁₃, —OSO₂R₃₁₄, —OC(O)R₄₁₂, —OC(O)NHR₄₁₃, or —OSO₂R₄₁₄.
 16. The compound of claim 15, wherein: R₂ is —OR₂₁₁; R₂₁₁ is hydrogen, alkyl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄; and R₂₁₂, R₂₁₃, and R₂₁₄ are independently alkyl or aryl.
 17. The compound of claim 15, wherein: R₃ is —OR₃₁₁; R₃₁₁ is hydrogen, alkyl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄; and R₃₁₂, R₃₁₃, and R₃₁₄ are independently alkyl or aryl.
 18. The compound of claim 15, wherein: R₄ is —OR₄₁₁; R₄₁₁ is hydrogen, alkyl, —C(O)R₄₁₂, —C(O)NHR₄₁₃, or —SO₂R₄₁₄; and R₄₁₃, and R₄₁₄ are independently alkyl or aryl.
 19. The compound of claim 15, wherein R₁₂ is alkyl, allyl, benzyl, or halo.
 20. The compound of claim 15, wherein R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₂, R₄₁₃, and R₄₁₄ are methyl.
 21. The compound of claim 15, wherein R₃ is methoxy, R₄ is hydroxyl, —OC(O)CH₂CH₃, or —OSO₂CH₃, R₆ is methoxy, and R₁, R₂, R₄, R₅, R₇, R₁₂, R₁₃ are hydrogen.
 22. The compound of claim 15, wherein: R₂ is —OR₂₁₁; R₂₁₁ is hydrogen, alkyl, —C(O)R₂₁₂, —C(O)NHR₂₁₃, or —SO₂R₂₁₄; and R₂₁₂, R₂₁₃, and R₂₁₄ are independently alkyl or aryl; R₃ is —OR₃₁₁; R₃₁₁ is hydrogen, alkyl, —C(O)R₃₁₂, —C(O)NHR₃₁₃, or —SO₂R₃₁₄; and R₃₁₂, R₃₁₃, and R₃₁₄ are independently alkyl or aryl; R₄ is —OR₄₁₁; R₄₁₁ is hydrogen, alkyl, —C(O)R₄₁₂—C(O)NHR₄₁₃, or —SO₂R₄₁₄; and R₄₁₃, and R₄₁₄ are independently alkyl or aryl.
 23. The compound of claim 22, wherein R₂₁₂, R₂₁₃, R₂₁₄, R₃₁₂, R₃₁₃, R₃₁₄, R₄₁₂, R₄₁₃, and R₄₁₄ are methyl; R₃ is methoxy, R₄ is hydroxyl, —OC(O)CH₂CH₃, or —OSO₂CH₃, R₆ is methoxy, and R₁, R₂, R₄, R₅, R₇, R₁₂, R₁₃ are hydrogen. 